miRNA-let7b5p alleviates visceral hypersensitivity by inhibiting the activation of spinal microglial in male IBS-like rats.

Abstract

Visceral hypersensitivity is a hallmark feature of irritable bowel syndrome (IBS), yet its underlying mechanisms remain incompletely understood. In the present study, we found that miRNA-let7b5p was downregulated in the spinal cord of IBS model rats induced by neonatal colorectal distension. Concurrently, microglia exhibited a shift toward a pro-inflammatory M1 phenotype and selectively engulfed inhibitory synapses, resulting in impaired GABAergic neuronal function and disruption of the excitatory/inhibitory balance. Intrathecal administration of a miRNA-let7b5p agomir suppressed M1-type microglial activation in the spinal cord, reduced pro-inflammatory cytokine levels, and alleviated visceral hypersensitivity, whereas antagomir treatment induced visceral hypersensitivity in control rats. Mechanistically, MAP3K3 was identified as a direct target of miRNA-let7b5p, and its knockdown recapitulated the protective effects conferred by miRNA upregulation. Collectively, these findings demonstrate that miRNA-let7b5p attenuates IBS-associated visceral hypersensitivity by downregulating MAP3K3, thereby inhibiting spinal microglial activation and restoring GABAergic neuronal function. This study provides novel insights into the pathogenesis of IBS-related visceral hypersensitivity and highlights a potential therapeutic target for drug development.